Alpha-methylated derivatives of 2-arachidonoyl glycerol: synthesis, CB1 receptor activity, and enzymatic stability

Alpha-methylated analogues of the endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), were synthesized aiming to the improved enzymatic stability of 2-AG. In addition, the CB1 activity properties of fluoro derivatives of 2-AG were studied. The CB1 receptor activity was determined by the [35S]GTPgammaS binding assay, and the enzymatic stability of alpha-methylated analogues was determined in rat cerebellar membranes. The results indicate that even if the alpha-methylated 2-AG derivatives are slightly weaker CB1 receptor agonists than 2-AG, they are clearly more stable than 2-AG. In addition, the results showed that the replacement of the hydroxyl group(s) of 2-AG by fluorine does not improve the CB1 activity of 2-AG.     

Arachidonylsulfonyl derivatives as cannabinoid CB1 receptor and fatty acid amide hydrolase inhibitors

Arachidonylsulfonyl fluoride (3), reported here for the first time, is similar in potency to its known methyl arachidonylfluorophosphonate (2) analogue as an inhibitor of mouse brain fatty acid amide hydrolase activity (IC(50) 0.1 nM) and cannabinoid CB1 agonist [3H]CP 55,940 binding (IC(50) 304-530 nM). Interestingly, 3 is much more selective than 2 as an inhibitor for fatty acid amide hydrolase relative to acetylcholinesterase, butyrylcholinesterase and neuropathy target esterase. N-(2-Hydroxyethyl)arachidonylsulfonamide (4) is at least 2500-fold less potent than N-(2-hydroxyethyl)arachidonamide (anandamide) (1) at the CB1 agonist site.     

Synthesis and biological activity of amide derivatives of nimbolide

Nimbolide (1), a limonoid isolated from Azadirachta indica, is the chief cytotoxic principle in Neem leaves extract. Using nimbolide as a lead compound for anti-cancer analogue design, a series of nimbolide derivatives have been synthesized and evaluated for in vitro cytotoxic activity against a panel of human cancer cell lines. Out of 10 compounds screened 2g, 2h and 2i showed potent activity.     

Synthesis and evaluation of anti-thrombotic activity of benzocoumarin amide derivatives

A series of novel benzocoumarin amide derivatives have been synthesized and evaluated for their anti-thrombotic activity. Amongst these, compounds 5, 7 and 8 exhibited promising anti-thrombotic profile in an established model of mouse thrombosis. Hence, comprehensive profiling on platelet aggregation and coagulation parameters was carried out to assess its potential as a lead candidate. In vitro treatment of these compounds in mice plasma resulted into significant reduction in ADP (p<0.01) and collagen (p<0.001) induced platelet aggregation. Moreover, Compounds 5, 7 and 8 also significantly increased thrombin time (p<0.05). Thus, in the present study, these benzocoumarin amide derivatives exhibited anti-thrombotic profile via both anti-platelet as well as anti-coagulant action.     

Synthesis and antimicrobial activity of amide derivatives of polyether antibiotic-salinomycin

For the first time a direct and practical approach to the synthesis of eight amide derivatives of polyether antibiotic-salinomycin is described. The structure of allyl amide (3a) has been determined using X-ray diffraction. Salinomycin and its amide derivatives have been screened for their in vitro antimicrobial activity against the typical gram-positive cocci, gram-negative rods and yeast-like organisms, as well as against a series of clinical isolates of methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus. Amides of salinomycin have been found to show a wide range of activities, from inactive at 256 μg/mL to active with MIC of 2 μg/mL, comparable with salinomycin. As a result, phenyl amide (3b) was found to be the most active salinomycin derivative against gram-positive bacteria, MRSA and MSSA.     

Synthesis and anticancer activity of novel amide derivatives of non-acetal deoxoartemisinin

Novel amide derivatives of C-12 non-acetal deoxoartemisinin were synthesized. Some of the derivatives had potent in vitro anticancer activity against major human cancer cell lines. The deoxoartemisinin amide trimer had potent in vivo antiangiogenic activity, according to the mouse matrigel plug assay.     

New metabolically stable fatty acid amide ligands of cannabinoid receptors: Synthesis and receptor affinity studies

We investigated the structure-activity relationships for the interactions of fatty acid amide analogs of the endocannabinoid anandamide with human recombinant cannabinoid receptors. Thirty-five novel fatty acid amides were synthesized using five different types of acyl chains and 11 different aromatic amine 'heads.' Although none of the new compounds was a more potent ligand than anandamide, we identified three amine groups capable of improving the metabolic stability of arachidonoylamides and their CB(1)/CB(2) selectivity ratio to over 20-fold, and several aromatic amines capable of improving the affinity of short chain or monosaturated fatty acids for cannabinoid CB(1) receptors. For the first time a tertiary amide of arachidonic acid was found to possess moderate affinity (K(i)=300 nM) for cannabinoid CB(1), but not CB(2), receptors.     

Structure, enzymatic stability and antitumor activity of sea lamprey GnRH-III and its dimer derivatives

Direct antitumor activity of sea lamprey (Petromyzon marinus) gonadotropin-releasing hormone III (Glp-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH(2); lGnRH-III) was described on several tumor cells. To improve the selectivity of antitumor effects without increasing the hormone releasing activity and to enhance the enzymatic stability, lGnRH-III dimers were prepared via disulfide bond formation. Our results demonstrate that the lGnRH-III dimer derivatives exhibited higher antiproliferative effect and enzymatic stability in comparison with the native lGnRH-III, while lower LH-releasing potency was determined. In order to find a correlation between the biological and structural features of these compounds, the conformation of lGnRH-III and its dimer derivatives was determined by ECD, VCD, FT-IR and (1)H NMR.     

Synthesis and pharmacological evaluation of coumarin derivatives as cannabinoid receptor antagonists and inverse agonists

In the present study we synthesized 36 coumarin and 2H-chromene derivatives applying a recently developed umpoled domino reaction using substituted salicylaldehyde and α,β-unsaturated aldehyde derivatives as starting compounds. In radioligand binding studies 5-substituted 3-benzylcoumarin derivatives showed affinity to cannabinoid CB₁ and CB₂ receptors and were identified as new lead structures. In further GTPγS binding studies selected compounds were shown to be antagonists or inverse agonists.     

Synthesis, anti-HIV activity, and stability studies of 5'-phosphorofluoridate derivatives of AZT

The synthesis, in vitro anti-HIV activity and stability studies of the 5'-fluorophosphate derivative of 3'-azido-3'-deoxythymidine (AZT) are reported. The results support the hypothesis that this phosphorylated entity exerts its biological effect via the delivery of the corresponding 5'-mononucleotide through an enzymatic process. However, the antiviral evaluation in thymidine kinase-deficient CEM cells as well as the stability studies in culture medium and cell extract showed that this bioconversion is not specific to the intracellular medium. Attempts to improve the biological activity of mononucleoside 5'-fluorophosphates by the use of the S-pivaloyl-2-thioethyl (tBuSATE) group as biolabile phosphate protection are reported.     

Synthesis, activity, metabolic stability, and pharmacokinetics of glucocorticoid receptor modulator-statin hybrids

The synthesis, activity, metabolic stability, and pharmacokinetics of steroidal and nonsteroidal glucocorticoid receptor modulator-statin hybrids is reported. Potent steroidal antagonist-statin hybrids like 22 (h-GR binding IC(50)=7 nM) and nonsteroidal modulator hybrids like 16 (h-GR binding IC(50)=2 nM) were discovered. Appending a 'statin'-like diol-acid group to the modulators dramatically improved metabolic stability (and in some cases hepatocyte activity), but did not impart hepatoselectivity.     

Synthesis and SAR of 1,3-disubstituted cyclohexylmethyl urea and amide derivatives as non-peptidic motilin receptor antagonists

A series of 1,3-disubstituted cyclohexylmethyl urea and amide derivatives were synthesized as motilin receptor antagonists. Starting from known motilin antagonists, 1a and 1b, the cyclopentene scaffold was replaced and the four recognition elements optimized to arrive at a potent novel series.     

Synthesis, binding studies and molecular modeling of novel cannabinoid receptor ligands

In the present work, we report upon the design, synthesis and biological evaluation of new anandamide derivatives obtained by modifications of the fatty acyl chain and/or of the ethanolamide 'tail'. The compounds are of the general formula: 6-(substituted-phenyl)/naphthyl-4-oxohex-5-enoic acid N-substituted amide and 7-naphthyl-5-oxohept-6-enoicacid N-substituted amide. The novel compounds had been evaluated for their binding affinity to CB1/CB2 cannabinoid receptors, binding studies showed that some of the newly developed compounds have measurable affinity and selectivity for the CB2 receptor. Compounds XI and XVIII showed the highest binding affinity for CB2 receptor. None of the compounds exhibited inhibitory activity towards anandamide hydrolysis, thus arguing in favor of their enzymatic stability. The structure-activity relationship has been extensively studied through a tailor-made homological model using constrained docking in addition to pharmacophore analysis, both feature and field based.     

Synthesis,molecular docking and anti-diabetic evaluation of 2,4-thiazolidinedione based amide derivatives

A series of thiazolidinedione based amide derivatives were designed, synthesized and docked against the PPARγ receptor target. 11 compounds from the series with good glide scores were selected for in vivo antidiabetic study based on streptozotocin induced diabetic rat model. It was observed that 4 compounds (6c, 6e, 6m & 6n) showed significantly good antidiabetic activity in comparison to rosiglitazone and pioglitazone as reference drugs. Compound 6c appeared as the most potent derivative in lowering blood glucose level and showed excellent interaction with SER 342, ILE 281, pi-pi interaction with ARG 288 and halogen bond interaction with LYS 367. Further, PPARγ transactivation and gene expression studies of compound 6c were carried out to investigate the possible mechanism of action through PPARγ modulation. Compound 6c exhibited 53.65% transactivation and elevated PPARγ gene expression by 2.1 folds. The biochemical parameters (AST, ALT and ALP levels) were found within the range with no noteworthy damage to liver.     

Synthesis and structure activity relationships of glycine amide derivatives as novel Vascular Adhesion Protein-1 inhibitors

Vascular Adhesion Protein-1 (VAP-1) is a promising therapeutic target for the treatment of several inflammatory-related diseases including diabetic microvascular complication. We identified glycine amide derivative 3 as a novel structure with moderate VAP-1 inhibitory activity. Structure-activity relationship studies of glycine amide derivatives revealed that the tertiary amide moiety is important for stability in rat blood and that the position of substituents on the left phenyl ring plays an important role in VAP-1 inhibitory activity. We also found that low TPSA values and weak basicity are both important for high PAMPA values for glycine amide derivatives. These findings led to the identification of a series of orally active compounds with enhanced VAP-1 inhibitory activity. Of these compounds, 4g exhibited the most potent ex vivo efficacy, with plasma VAP-1 inhibitory activity of 60% after oral administration at 1 mg/kg.     

Synthesis and evaluation of novel antifungal agents-quinoline and pyridine amide derivatives

Quinoline amide, azaindole amide and pyridine amides were synthesized and tested for in vitro antifungal activity against fungi. These synthesized amides have potent antifungal activity against Candida albicans and Aspergillus fumigatus. Our results suggest that hetero ring amides may be potent antifungal agents that operate by inhibiting the function of Gwt1 protein in the GPI biosynthetic pathway.     

Diarylimidazolyl oxadiazole and thiadiazole derivatives as cannabinoid CB1 receptor antagonists

Since the CB1 receptor antagonist SR141716 (rimonabant) was reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target in the treatment of obesity. Several series of derivatives based on diarylimidazolyl oxadiazole and thiadiazole scaffolds were synthesized and tested for CB1 receptor binding affinity. SAR studies directed toward the optimization of imidazole scaffolds resulted in the discovery of 10s which showed highest potency for CB1 receptor binding affinity (IC₅₀ = 1.91 nM) prepared to date.     

Synthesis of tripeptide RGD amide by a combination of chemical and enzymatic methods

The tripeptide Bz-Arg-Gly-Asp(NH₂)OH was synthesized by a combination of chemical and enzymatic methods in this study. Firstly, Gly-Asp-(NH₂)₂ was synthesized by a novel chemical method in three steps including chloroacetylation of l-aspartic acid, esterification of chloroacetyl l-aspartic acid and ammonolysis of chloroacetyl l-aspartic acid diethyl ester. Secondly, the linkage of the third amino acid (Bz-Arg-OEt) to Gly-Asp-(NH₂)₂ was completed by enzymatic method under kinetic control condition. An industrial alkaline protease alcalase was used in water–organic cosolvents systems. The synthesis reaction conditions were optimized by examining the effects of several factors including water content, temperature, pH and reaction time on the yield of the synthesis product Bz-Arg-Gly-Asp(NH₂)OH. The optimum conditions are pH 8.0, 35 °C, in ethanol/Tris–HCl buffer system (85:15, v/v), 8 h with the tripeptide yield of 73.6%.     

Synthesis of novel amide and urea derivatives of thiazol-2-ethylamines and their activity against Trypanosoma brucei rhodesiense

2-(2-Benzamido)ethyl-4-phenylthiazole (1) was one of 1035 molecules (grouped into 115 distinct scaffolds) found to be inhibitory to Trypanosoma brucei, the pathogen causing human African trypanosomiasis, at concentrations below 3.6 μM and non-toxic to mammalian (Huh7) cells in a phenotypic high-throughput screen of a 700,000 compound library performed by the Genomics Institute of the Novartis Research Foundation (GNF). Compound 1 and 72 analogues were synthesized in this lab by one of two general pathways. These plus 10 commercially available analogues were tested against T. brucei rhodesiense STIB900 and L6 rat myoblast cells (for cytotoxicity) in vitro. Forty-four derivatives were more potent than 1, including eight with IC₅₀ values below 100 nM. The most potent and most selective for the parasite was the urea analogue 2-(2-piperidin-1-ylamido)ethyl-4-(3-fluorophenyl)thiazole (70, IC₅₀ = 9 nM, SI > 18,000). None of 33 compounds tested were able to cure mice infected with the parasite; however, seven compounds caused temporary reductions of parasitemia (⩾97%) but with subsequent relapses. The lack of in vivo efficacy was at least partially due to their poor metabolic stability, as demonstrated by the short half-lives of 15 analogues against mouse and human liver microsomes.     

Synthesis of water-soluble retinol derivatives by enzymatic method

Retinoids (vitamin A and derivatives) are of great commercial potential in cosmetics and pharmaceuticals such as skin care products. However, the clinical effectiveness of these retinoids is limited by skin irritation, water insolubility, and except for retinyl-esters, extreme instability. In this paper, an enzymatic method for preparing water-soluble retinol derivatives catalyzed by immobilized lipase is described. The synthesis is based on a unique strategy of two-step enzymatic acylation. Among the different synthesized compounds, the most water-soluble are the disaccharide derivatives such as saccharose retinyl adipate (nonionic water-soluble retinol derivative) and the sodium salt of retinyl diacids such as retinyl succinate sodium salt (ionic water-soluble retinol derivative).